Tobacco smoke is the major cause of lung cancer, the most common type of fatal cancer worldwide. A possible means by which tobacco smoke exerts its carcinogenic effect is the DNA damage produced by the generation of reactive oxygen species and the formation of DNA adducts. Since the majority of persons who smoke tobacco do not develop lung cancer, it is possible that those who do develop this disease have a relatively poor capacity to repair the DNA damage that results from smoking. In a nested case-control study, we plan to determine whether polymorphisms of enzymes involved in the repair of smoking-induced DNA damage, namely those from the base excision (BER) and nucleotide excision repair (NER) pathways, are associated with risk of lung cancer. We propose to genotype the functional single nucleotide polymorphisms (SNPs) as well as tagging SNPs of 25 DNA repair genes (a total of 331 polymorphisms), that have been resequenced by the Seattle Variation Discovery Resource for the Environmental Genome Project. The lung cancer cases (n = 900) and controls (n = 1800) for the proposed study will come from the participants in the Carotene and Retinol Efficacy Trial (CARET) of lung cancer prevention. Genotyping of cases and controls will utilize DNA extracted from frozen whole blood samples. Detailed quantitative information on smoking and dietary history (using a food frequency questionnaire), obtained prior to the diagnosis of lung cancer, is available through CARET records. Cases and controls will be compared with respect to the prevalence of putative "high risk" genotypes, alone and in combination with other putative "high risk" genotypes within each pathway and in the two pathways combined. Analyses will also examine whether inferred haplotypes and their combinations are associated with risk. We will assess whether associations differ by histologic subtypes and sex. Results will be interpreted with multiple comparisons taken into account. The proposed study has sufficient statistical power to identify interactions between some of the high-risk genotypes/haplotypes, and to investigate whether the risk associated with a particular genotype/haplotype varies by other risk factors, such as smoking intensity and recency, and dietary factors, such as intake of antioxidant-rich fruits and vegetables (e.g. Rosaceae fruits and Cruciferae vegetables), and food-derived nutrients (e.g. carotenoids, vitamin C, and vitamin E).